Our bodies turn the food we eat into the sugar glucose. Blood transports glucose to cells which convert it into energy. Normally, a protein hormone called insulin controls the level of glucose in the blood. When there are defects in insulin production, insulin action, or both, high levels of glucose in the blood result. Diabetes is the group of diseases characterized by these defects.
The three most common forms of diabetes are type 1 diabetes, type 2 diabetes and gestational diabetes. Type 1 diabetes (previously known as insulin-dependent diabetes mellitus or juvenile-onset diabetes) usually develops in childhood or adolescence. It occurs when the body's immune system destroys the cells of the pancreas that produce insulin. People with type 1 diabetes must monitor the level of sugar in their blood multiple times a day and take insulin (via injections or a pump) to maintain an appropriate level. Gestational diabetes occurs when pregnant women become intolerant to glucose. Gestational diabetes also requires treatment to maintain appropriate glucose blood levels and avoid complications in the infant. Woman who have gestational diabetes are at increased risk for developing type 2 diabetes.
Type 2 diabetes (previously known as non-insulin-dependent diabetes mellitus or adult-onset diabetes) usually develops in adulthood. It develops as cells first do not use insulin properly and then the pancreas loses its ability to produce insulin. Many people with type 2 diabetes control their blood glucose with a meal plan, exercise program, losing weight and taking oral medication. Some people with type 2 diabetes need take insulin as well.
Diabetes is serious because too much sugar in the blood can damage the eyes, kidneys, nerves and heart. Complications of diabetes include heart disease, stroke, hypertension, blindness, other eye problems (such as diabetic retinopathy), kidney disease, nervous system disease (such as impaired sensation or pain in the feet or hands, slowed digestion of food, carpal tunnel syndrome and erectile dysfunction), amputations, periodontal disease, susceptibility to other illnesses (such as pneumonia and influenza), impaired mobility and depression. Uncontrolled diabetes can result in acute life-threatening events such as diabetic ketoacidosis and hyperosmolar coma.
Diabetes is the leading cause of kidney failure, non-traumatic lower limb amputations and new cases of blindness among adults in the United States. Diabetes is a major cause of heart disease and stroke. Diabetes was the seventh leading cause of death in the United States in 2007. Overall, the risk for death among people with diabetes is about twice that of people of similar age without diabetes. According to the Centers for Disease Control and Prevention, as of January 2011, diabetes affects 25.8 million people, 8.3% of the United States population. Another 79 million American adults are estimated to have prediabetes, a condition in which blood sugar levels are higher than normal but not high enough to be diagnosed as diabetes. Prediabetes is sometimes called impaired fasting glucose or impaired glucose tolerance. Prediabetes itself raises people's risk of type 2 diabetes, heart disease and stroke. Many prediabetics develop type 2 diabetes within ten years.
In addition to lifestyle interventions, prediabetic and type 2 diabetic patients are often treated with medications to address complications of diabetes. Doctors prescribe medications to control blood pressure and blood lipids to reduce cardiovascular complications. Often, in younger and heavier patients with normal kidney function, doctors prescribe the oral drug metformin to more directly address the defects causing diabetes. Metformin suppresses hepatic glucose production, increases insulin sensitivity, enhances peripheral glucose uptake, increases fatty acid oxidation and decreases absorption of glucose from the gastrointestinal tract. Metformin, though, is contraindicated in people with any condition that could increase the risk of lactic acidosis, including kidney disorders, lung disease and liver disease.
Other more recently approved drugs do not appear to be more effective than metformin and each has its own set of contraindications. For example, rosiglitazone was one of the first insulin-sensitizers used as an anti-diabetic drug. It renders fat cells more sensitive to insulin. Annual sales of rosiglitazone peaked at approximately $2.5 billion in 2006. Because rosiglitazone can be associated with an increased risk of cardiovascular events, the European Medicines Agency recommended the drug be suspended from the European market. The U.S. Food and Drug Agency has allowed it to remain on the market but it became subject to significant restrictions as of Sep. 23, 2010.
A precursor to insulin called human proinsulin C-peptide, and fragments of C-peptide, have also been investigated for the treatment of diabetes. See, International Publication Nos. WO 98/13384, WO 2002/022211, WO 2004/016647, WO 2006/129095 and WO 2007/015069. See also, Ohtomo et al., Diabetologia, 41: 287-291 (1998); Sato et al., Cell. Mol. Life. Sci., 61: 727-732 (2004); Hach et al., Exp. Diabetes Res.: 1-6 (2008) and Ido et al., Science, 277: 563-566 (1997).
Food proteins are composed of twenty different amino acids and scientists have studied the effect of individual amino acids when ingested with glucose. See, Gannon and Nuttall, IUBMB Life, 62: 660-668 (2010); Gannon et al., Metabolism, 37: 1081-1088 (1988); Gannon et al., Am. J. Clin. Nutr., 76: 1302-1307 (2002) and Kalogeropoulou et al., Metabolism, 57: 1747-1752 (2008). The amino acids leucine and glycine have been reported to attenuate the serum glucose response and stimulate additional insulin secretion. This effect requires the ingestion of significant amounts of the amino acids though, with accompanying bad taste, unbalanced amino acid intake and concerns of impairing renal function.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone. Incretin hormones are secreted by intestinal cells in response to nutrient ingestion. The primary physiological function of GLP-1 appears to be related to glycemic control. GLP-1 stimulates insulin release, inhibits glucagon secretion, reduces gastric emptying and augments satiety. In patients with type 2 diabetes the incretin effect is reduced, contributing to impaired glycemic control. Administration of GLP-1 to patients has been reported to restore blood glucose regulation via endogenous insulin secretion. GLP-1 administration has also been reported to reduce energy intake through its actions of delaying gastric emptying and increasing satiety, therefore it may induce weight loss. Two GLP-receptor agonists/analogues are currently approved for treatment of type 2 diabetes mellitus, exenatide (Byetta®), and liraglutide (Victoza®) and others are in clinical development. A once-weekly formulation of exenatide (Bydureon®) has also been approved. See, Barnett et al., Diabetes, Obesity and Metabolism. accepted article published online (2011).
In addition, studies have demonstrated that agonists of the GLP-1 receptor also effect cardiovascular related functions such as heart rate and blood pressure. See, Grieve et al., British J. Pharm., 157a: 1340-1351 (2009). In a particular study, Dahl salt-sensitive (DSS) rats were fed a high salt diet and treated with an exenatide mimetic (AC3174) alone or in combination with an ACE inhibitor (captopril). AC3174 had anti-hypertensive, insulin-sensitizing, and renoprotective effects comparable to that of captopril. See, Liu et al., Cardiovascular Diabetology, 9(32): 1-10 (2010).
There thus exists a need in the art for new treatments for prediabetes, diabetes and their complications. There also exists in the art a need for new treatments for obesity, high blood pressure and metabolic syndrome.